Chronic over-nutrition and dysregulation of GSK3 in diseases
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REVIEW
Open Access
Chronic over-nutrition and dysregulation of GSK3 in diseases Xunxian Liu and Zemin Yao*
Abstract Loss of cellular response to hormonal regulation in maintaining metabolic homeostasis is common in the process of aging. Chronic over-nutrition may render cells insensitive to such a hormonal regulation owing to overstimulation of certain signaling pathways, thus accelerating aging and causing diseases. The glycogen synthase kinase 3 (GSK3) plays a pivotal role in relaying various extracellular and intracellular regulatory signals critical to cell growth, survival, regeneration, or death. The main signaling pathway regulating GSK3 activity through serine-phosphorylation is the phosphoinositide 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/Akt relay that catalyzes serinephosphorylation and thus inactivation of GSK3. In addition, perilipin 2 (PLIN2) has recently been shown to regulate GSK3 activation through direct association with GSK3. This review summarizes current understanding on environmental and nutritional factors contributing to GSK3 regulation (or dysregulation) through the PI3K/PDK1/Akt/GSK3 axis, and highlights the newly discovered role that PLIN2 plays in regulating GSK3 activity and GSK3 downstream pathways.
Background Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase [1] and catalyzes phosphorylation of perhaps more than 100 substrates [2]. A unique feature associated with GSK3 regulation is that the enzyme is “constitutively” activated (i.e. always in the “on” stage”) in cells [3], probably due to a recently identified phosphorylation of GSK3 catalyzed by protein kinase (PK) Cζ [4]. Physiological inhibitors of GSK3 include phosphoinositide 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/Akt relay [5], as well as the newly identified lipidbinding protein perilipin 2 (PLIN2), also known as adipose differentiation-related protein (ADRP) [6]. In the PI3K/PDK1/Akt relay, Akt is activated by PDK1 [7], and PDK1 in turn is activated by PI3K-generated 3phosphorylated phosphoinositides [8]. In this review, the PI3K/PDK1/Akt axis involved in GSK3 inhibition is abbreviated as PI3K/Akt pathway. Because PI3K activities are modulated by a variety of factors, including hormones, lipid, drugs, food components and food metabolic products through their respective receptors [9], the PI3K/Akt/GSK3 axis represents a major regulatory pathway that relays extracellular and * Correspondence: [email protected] Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
intracellular signals critical to cell growth, survival, regeneration, or death. It is thus generally believed that negative regulation of GSK3, through PI3K/Akt-mediated phosphorylation, keeps GSK3 activity at “off” or “low” stages [2]. Under disease conditions, either genetic abnormalities or unhealthy environmental factors (such as life style, habits, psychology, and medication) can break cellular home
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